Changes in relative potency among positive GABAA receptor modulators upon discontinuation of chronic benzodiazepine treatment in rhesus monkeys

Abstract

These results suggest that positive GABA(A) receptor modulators acting at different sites attenuate withdrawal induced by discontinuation of benzodiazepine treatment, consistent with previous studies suggesting that the same compounds attenuate flumazenil-precipitated withdrawal. Differences in the relative potency of positive modulators as a function of acute versus chronic benzodiazepine treatment suggest that neuroactive steroids, in particular, are especially potent in benzodiazepine-dependent animals.

Acute cross tolerance to midazolam, and not pentobarbital and pregnanolone, after a single dose of chlordiazepoxide in monkeys discriminating midazolam

“…In fact, under those treatment conditions, sensitivity to pregnanolone increased 3-fold. Decrease sensitivity to benzodiazepines with concomitant enhanced sensitivity to neuroactive steroids has also been observed in monkeys receiving diazepam chronically (McMahon and France 2002b; McMahon et al 2007), and these similarities in effects obtained following acute and chronic treatment suggest that the same mechanism might be responsible for these changes under both treatment conditions. There are several possible explanations for these qualitatively different effects between benzodiazepines and neuroactive steroids.…”

“…Similar effects were obtained in the current study; acute cross tolerance to midazolam developed in monkeys that received chlordiazepoxide 24 hr earlier. Acute cross tolerance to positive GABA A modulators acting at other sites has not been established, although chronic benzodiazepine treatment does not appear to confer cross tolerance to neuroactive steroids (Czlonkowska et al 2001; McMahon and France 2002b; McMahon et al 2007). In the current study, acute cross tolerance did not develop to pregnanolone under conditions that decreased sensitivity to midazolam.…”

“…Specifically, although tolerance to benzodiazepines can be readily established in the laboratory, tolerance to neuroactive steroids is much more difficult to demonstrate and does not develop under many conditions (Kokate et al 1998; Reddy and Rogawski 2000; Damianisch et al 2001; McMahon and France 2002a). In addition, during chronic benzodiazepine treatment, sensitivity to benzodiazepines decreases, indicating the development of tolerance or cross tolerance, whereas sensitivity to neuroactive steroids does not appear to change (Czlonkowska et al 2001; McMahon and France 2002b; McMahon et al 2007). This differential development of tolerance and cross tolerance to positive GABA A modulators suggests that changes in GABA A receptors during chronic treatment impact modulatory sites differently.…”

“…This study tested the generality of effects obtained during chronic benzodiazepine treatment (e.g., Czlonkowska et al 2001; McMahon and France 2002b; McMahon et al 2007) by examining acute cross tolerance to positive GABA A modulators (Barrett and Smith 2005). Although long-term benzodiazepine treatment clearly produces cross tolerance to positive modulators acting at benzodiazepine sites and not those acting at neuroactive steroid sites (Czlonkowska et al 2001; McMahon and France 2002b), it is not clear whether much shorter periods of treatment also alter potency of positive modulators differentially depending on their site of action.…”

Neuropharmacology of the Interoceptive Stimulus Properties of Nicotine

“…Drug discrimination has been used widely to characterize the discriminative effects of withdrawal from d -amphetamine [169], benzodiazepines [170, 171], opioids [172, 173], and Δ 9 -THC [174]. Although studies of nicotine dependence/withdrawal have relied primarily on somatic (e.g., somatic signs) or affective (e.g., conditioned place aversion, intracranial self-stimulation) measures, it seems plausible that rats could learn to discriminate injections of a nAChR antagonist (e.g., mecamylamine) following acute nicotine pretreatment or during chronic nicotine exposure.…”